Alkanoate esters of n-mercaptoalkyl oxyalkyl amines



United States Patent 3,410,889 ALKANOATE ESTERS OF N-MERCAPTOALKYLOXYALKYL AMINES John C. James, Potomac, Md., Robert J. Wineman, Concord,Mass., and Morton H. Gollis, deceased, late of Brookline, Mass., byBernard Gollis, administrator, Brookline, Mass., assignors to MonsantoResearch Corporation, St. Louis, Mo., a corporation of Delaware NoDrawing. Application Nov. 24, 1964, Ser. No. 413,953, now Patent No.3,356,730, dated Dec. 5, 1967, which is a continuation-in-part ofapplication Ser. No. 176,409, Feb. 28, 1962. Divided and thisapplication Oct. 27, 1967, Ser. No. 679,294

' 6 Claims. (Cl. 260455) This application is a divisional of ourcopending application, S.N. 413,953 filed Nov. 24, 1964, now Patent No.3,356,730 which is a continuation-in-part of our copending applicationS.N. 176,409 filed Feb. 28, 1962 now Patent No. 3,341,577.

This invention relates to new chemical compounds, and more particularly,provides novel mercaptoalkyl oxyalkyl amines.

Aliphatic mercaptoalkyl oxyalkyl amines in which at least one of theamino N and oxy O atoms is exocyclic have not been known heretofore.Where these atoms are exocyclic, they can exert effects such asmodifying the polarity, basicity and hyd-rophilicity of the compoundswhich are not observed when they form part of the same ring, and onlythe mercaptoalkyl group is eXocyclic. Also, one or both of the amino Nand oxy O atoms may carry hydrogen as a substituent, and thereby besusceptible of activity such as hydrogen bonding in a biological system,chemical reactivity and the like. These factors may produce protectiveefiects in biological systems at sublethal levels.

It is an object of this invention to provide novel compounds.

A particular object of this invention is to provide novel mercaptoalkyloxyalkyl amines in which at least one of the amino N and oxy O isexocyclic.

Another object is to provide a novel method of protecting biologicalorganisms from harmful conditions.

These and other objects will become evident from a consideration of thefollowing specification and claims.

The compounds provided by this invention are N- mercaptoalkyl oxyalkylamines in which at least one of the amino N and oxy O atoms isexocyclic; and alkanoate esters and acid addition salts thereof.

It has been found that administration of compounds of the stated type asdescribed hereinafter protects biological organisms from the 'harmfuleffects of ionizing radiation.

The amines of this invention, by which is meant the said mercaptoalkylamines as distinguished from their esters and acid addition salts, maybe described as N- mercaptoalkyl oxyalkyl amines containing from 1 to 2amino nitrogen atoms, and from 1 to 2 oxyalkyl radicals and from 1 to 2mercaptoalkyl radicals attached to said nitrogen atoms, at least one ofsaid oxy oxygen and said amino nitrogen atoms being exocyclic.

The invention includes a number of different types of mercaptoalkyloxyalkyl amines, a comprehension of which will be facilitated byconsideration of the specific classes included herein as follows.

A first class of compounds provided hereby are monoamines of the formulawhere each R is saturated aliphatic hydrocarbon, each Patented Nov. 12,1968 R is selected from H and saturated aliphatic hydrocarbon and x isan integer of from 1 to 3.

By each R is means R and R and by each R, R' and R and so forth.

If R' is H, these are alcohols. Embodiments of the invention includesecondary amino and tertiary amino mono-alkanols and polyalkanols aspointed out hereinafter, such as If R is hydrocarbon, the embodiment ofthe invention is an ether, such as Where x is 2 or 3, the R' groups maybe different, one being H and one aliphatic hydrocarbon, representingthe embodiment of the invention comprising alkoxy alkanols, such as oreach R' may be the same, providing embodiments of the invention such aspolyols like An embodiment of the invention included in the abovestatedgroups comprises alicyclic compounds, such as A further embodiment ofthis invention comprises heterocyclic alcohols and ethers, where two ofthe radicals symbolized in R' R and R are aliphatic hydrocarbon formingpart of the same chain. These alcohols and ethers may be azacyclic, suchas A second class of amines provided by this invention comprisesdiamines.

In a first embodiment of this class, the said diamines arealkylenediamines in which one of the amine nitrogen atoms is attached toa mercaptoalkyl radical, one of the nitrogen atoms is attached to anoxyalkyl radical, and all the other nitrogen substituents of thediamines are selected from H and saturated aliphatic hydrocarbons. Theseare represented by the formulas:

HSR11TIR3NR2 0 R'z) X R'i 's and HS-R1NR2IIIR4 R'i 5k R: where each R issaturated aliphatic hydrocarbon,

each R is selected from the class consisting of hydrogen and saturatedalphatic hydrocarbon, and x is an integer of from 1 to 3.

Like the above mono-amines, this class of diamines includes alcohols andethers. Illustrative of such alcohols are the diamines of the aboveformula which are mercaptoalkylamino oxyalkylamines, with the oxyalkylradical attached to both notrogens, such asHS-CHzCHg-NH-OT-ECHCIii-Moment):

The embodiment of these diamines where the oxyalkyl radical is attachedto one nitrogen and the mercaptoalkyl to the other may be illustrated byan ether such as In a second embodiment of the class of diamines of thisinvention, the diamines are bis-N-mercaptoalkyl oxyalkanediamines. Theyare represented by the general formula where each R is saturatedaliphatic hydrocarbon, each R is selected from H and saturated aliphatichydrocarbon, and x is an integer of from 1 to 3.

These diamines are illustrated, for example, by a member of the groupcomprising alkanediols of the stated type, such as From the foregoing itwill be evident that the present amines can be generally described asmercaptoalkyl oxyalkyl monoand di-amines in which at least one of theoxy O and amino N atoms is exocyclic, and in which all the nitrogensubstituents are selected from the class consisting of H, saturatedaliphatic hydrocarbon, oxyalkyl and mercaptoalkyl radicals. Oxydesignates connective oxygen, joining C to H or forming the sole bondbetween two C atoms; the presently provided amines are completelysaturated, and free of C and CN unsaturation as well as ofcarbon-to-carbon unsaturation. Further characterizing the amines of thisinvention is the fact that the nitrogen atoms thereof are at least twocarbon atoms removed from hetero atoms (atoms other than C, including 0and S). The 2-mercaptoalkyl and 3-mercaptoalkyl amines are preferred,and the compounds in which the nitrogen atom is beta to each of asulfur-substituted carbon atom and an oxygen-substituted carbon atom areespecially preferred. A particularly preferred class of the presentamines comprises the compounds in which at least one of the O and Natoms is hydrogen substituted.

As noted above, this invention also provides esters of the statedamines. This includes esters of one or both of the mercaptan functionand of the hydroxy function, where it is present in these amines, Theesters included are those of these amines with alkanoic acids, that is,acids consisting of a saturated aliphatic hydrocarbon radical attachedto the carboxylic function.

Each of the saturated aliphatic hydrocarbon radicals of the amines andtheir esters of this invention is hydrocarbon of up to 18 carbon atoms.

The acid addition salts of the compounds of this invention include saltsof the stated amines and of their esters. The acid used to form thesesalts may be inorganic or organic protonic acids, of the usual typeemployed in the art to form amine salts, such as hydrochloric andhydrobromic, for example. Physiologically acceptable salts of the amineswith non-toxic acids, such as the hydrochlorides, are preferred. Thepresently provided compounds are useful as pharmaceuticals; they areantiradiation drugs which protect animals against the lethal and toxiceffects of ionizing radiation.

The scope of the present invention will be best preciated from aconsideration at this point of the following examples, which areillustrative but not limiting. In these examples, all parts are byweight unless otherwise noted.

EXAMPLE 1 This example illustrates the compounds provided by thisinvention, by a tabular list of formulas, methods of preparation (Prep.)and characterizing properties of such compounds. In the tables, methodsof preparation are indicated as A, B or C. Briefly, method A is reactionof an oxyalkylamine with ethylene sulfide; method B is reaction of abenzylthioalkylamine with an alkylene epoxide followed by debenzylation;and method C is reaction of a benzylthioalkyl halide with anaminoalkanol followed by debenzylation. These methods are discussed morein detail hereinafter. Properties of the compounds tabulated refer tothe hydrochloride salt of the amine Where so indicated by the symbolHCl. Melting and boiling points are given in C. :and millimeters (mm)pressure; hyg. means hygroscopic and dec. means decomposition.

, Prep. Properties HS(CH2)z-NHCHz-CH;OH A Solid, m. -60; 1101 an oil, n1.557.

HS-(CHz)a-NHCH2CHzOH C HCl hyg. oil.

HS-(CHzh-NH-CHz-CHzOH OH A Solid b. /0.1 mm.; HCI an oil.

HS-(CHz) aNH-CHz-CH:CHCH2OH A Liquid, b. 8086/0.02 mm., 11 1.5150; HG]an oil.

HS-(CH2) 2-*NHCHOH:OH A Liquid, b. 8388/0.25 mm., 11,," 1.5036; H01 hyg.oil, b. 300".

CH CH;

HS(CH2) 2-'NHCH2(|3HCH3 B HCI v. hyg. semi-solid, m. 50.

HS(CH2)3-NH-CH2CHCH3 O HCI v. hyg. solid, 111. aboutHS-(CHzh-NH-CHg-CHCHzCH; B H01 v. hyg. solid, m. 83-91.

HS-(CHzh-NH-CHz-CHCIhCH; B H01 111. -154".

HS(CHz):NHCHz-CH(CH2)50H: B H01 m. 154-156".

TBS-(CH2) r-NH-CH-CHCH; A B. 64G7/0.1mm., 710 1.4985; 11 Cl hyg. solid,in. 60-62.

CH3 OH HGl n. 72-74".

EXAMPLE 2 EXAMPLE 3 This example describes a procedure in the scope ofmethod A for preparation of one of the amines of this invention, wherethe initial amine is too polar to have significant solubility inbenzene.

A 10% by volume solution of ethanol and benzene is prepared by combining320 parts by volume of ethanol with 2880 parts by volume of benzene, andthis mixture is dried azeo-tropically by refluxing. Then 560 parts byweight of 2-aminoethanol is added to the solvent mixture and refluxingto dry the reaction mixture is continued. When the system has beensubstantially freed of water, introduction of ethylene sulfide isinitiated, by dropwise addition of a solution of ethylene sulfide inbenzene until 55 parts by weight of ethylene sulfide has been added overa period of between 3 and 4 hours. Refiuxing is continued after theaddition is complete for an hour and then solvent is removed from thereaction mixture by heating under vacuum. The clear oily residue isdistilled and the fraction boiling at between 66 and 72 C column headtemperature of 0015-0025 mm. is recovered. This is2-[(Z-mercaptoethyl)amino]-ethanol. It is a solid at room temperature,melting at about 5560 C.

Proceeding similarly, ethylene sulfide is reacted withl-amino-3-diethylamino-2-propanol to provide l-diethylamino-3-(Z-mercaptoethyl) amino] -2-propanol.

EXAMPLE 4 This example describes preparation of the acid addition saltof an amine.

A solution of 37 parts of 2-[(2-mercaptoethyl)amino]- ethanol, preparedas described in Example 3, in 100 parts of water is blanketed withnitrogen, and the solution is stirred while 6 N hydrochloric acid isadded until just suflicient has been introduced to make the solutionacid. Then water is removed and the oily residue dried. The product isthe hydrochloride salt of 2-[(2-mercaptoethyl)amino]ethanol, an oil, n1.5570.

Another useful technique for preparation of the amine salts of thisinvention comprises dissolving the amine in an organic solvent such asethanol and adding acid thereto, employing a non-aqueous system. Forexample, dry hydrogen chloride may be passed as a gas into an ethanolsolution of the amine, until the solution is saturated.

One or the other of the stated methods is employed to prepare thehydrochloride salts of the amines shown in the above table.

EXAMPLE This example illustrates the formation of a2-[(benzylthio)alkylamino]alkanol in accordance with Method B of theinvention.

A solution of 125 parts of 2-(benzylthio)ethylamine in methanol ismaintained under a blanket of nitrogen and rapidly stirred while it isheld at a temperature of 45- 50 C. and about 40 parts of propylene oxideare introduced. The reaction mixture is held for another half hour at50, and then solvent is removed by evaporation to leave a colorless oil.The oil is distilled through a Vigreaux column and the fraction boilingat about 146 C. column head temperature at 0.05 mm. is recovered. Theproduct is l-([2-(benzylthio)ethyl]amino)- 2-propanol. The oily amine isconverted to the hydrochloride by dissolving a sample of the oil inabsolute ethanol, saturating the solution with dry HCl and addinganhydrous ether to precipitate the acid addition salt.

Proceeding similarly, employing the appropriate alkylene oxide and2-benzylthioethylamine or 3-benzylthiopropylamine, the followingbenzylthioalkylamines are prepared.

1-( [Z-ben'zylthio) etlhyl] amino) -2-butanol, b.

146-147/0.07 mm., n 1.5448, d, 1.060

1-( [3-(benzylthio) propyl]amino)-2-butanol, b.

152-153/0.10 mm, n 1.5447, d 0.051

1-([2-(benzylthio)ethyl1amino)-2-octanol, b.

166-168/0.02 mm., m. 5052 1-( [Z-(benzylthio ethyl] amino)-2-methyl-2-propanol,

b. 125-127/0.04 mm., m. 53-56 2-( [Z-(benzylthio) ethyl] amino)cyclohexanol, b.

164160/0. 07 mm., m. 6869 l,4-bis( [2- (benzylthio ethyl] amino)-2,3-butanediol,

1-( [2-benzylthio) ethyl]amino -3-butoxy-2propan0l,

propanol, b. l57/0.l5 mm., m. 8486 1-( benzylthio ethyl] amino) -3-butoxy-2-propanol,

b. 165l6'6/ 0.06 mm. l-( [2- (benzylthio ethyl] amino)-3-pentoxy-2-propanol,

b. 173-174/0.04 mm., n 1.5255, d 1.043

EXAMPLE 6 This example illustrates preparation of a benzylthioalkylamine in accordance with method C of this invention.

A reaction mixture is prepared by combining 185 parts of benzyl2-chloroethyl sulfide and parts of l-amino- 2-propanol in ethanol withabout 65 parts of sodium carbonate. The reaction mixture is refluxedunder nitrogen for 18 hours. The solvent is removed, water is added, andconcentrated HCl is then introduced to bring the solution to an acid pH.The acidic mixture is extracted with ether and the resulting aqueouslayer neutralized with 50% aqueous NaOH to form an oil which isextracted with ether. The extract is dried over sodium sulfate, theether is removed and the oil distilled. The fraction distilling over at133-135 C./-0.13 mm. column head temperature is dissolved in ethanol,and the solution is saturated with dry HCl. Addition of ether andchilling precipitates the hydrochloride salt of1-([2(benzylt-hio)ethyl-amino) 2 propanol. This hydrochloride salt meltsat 107108 C. A mixed melting point of this hydrochloride salt and thehydrochloride prepared as described in Example 5 is the same, thuscorroborating the structure assigned to the product of Example 5. Thesa'lts also have identical infrared spectra.

Using a substantially similar procedure, reaction of benzyl2-chloroethylsulfide or benzyl 3-chloropropyl sulfide with appropriateamines produces the following oxyalkyl benzylthioalkyl amines:

2-( [3-(benzylthio) propyl] amino)ethanol, b.

l49-15l/0.l0 mm., n 1.5635, df L091 1- [3- (benzylthio propyl]amino-Z-propanol, n

2-([2 (benzylthio)ethyllmethylamino)ethanol, n

2-( [3- (benzylthio)=propyl]methylamino) ethanol, b.

2-( [2- (benzylthio ethyl] isopropylamino ethanol, b.

142/0.15 mm., n 1.5393, d 1.042

2- [2- benzylthio) ethyl] -n-butylamino) ethanol,

3-( [2-(benzylthio) ethyl]amino)-l,2-propanediol, b.

180-190/0.1 mm., n 1.5710

3- [2- (benzylthio ethyl] amino) -2-hydroxymethyl- 1,3-propanediolhydrochloride, m. l08ll0 EXAMPLE 7 This example illustrates conversionof a benzylthioalkyloxyalkylamine prepared as described in Examples 5and 6 to the corresponding mercaptan, in accordance with Methods B and Cof this invention.

Enough sodium is added to anhydrous liquid ammonia to produce thecharacteristic blue color of sodium in liquid ammonia and then 45 partsof l-([2-benzylthio) ethyl]-arnino-2-butanol is mixed with the ammoniaand 9 parts of sodium are added, portion-wise, to the ammonia over aperiod of about an hour. Addition of the last of the sodium after thelast of the amine causes its blue color to persist, showing completionof the reaction. Ammonia is now removed by evaporation leaving a residueof finely divided powder. The residue is stirred in an ice bath while itis acidified with aqueous HCl. An oily layer is separated and discarded,the acidic mixture is extracted with ether, and the ether extracts arediscarded. The aqueous layer is then filtered, and evaporated down. Theresidue from this procedure is extracted with isopropanol and theextract concentrated to give a white waxy solid, very soluble inalcohols ranging from methanol to butanol and in acetonitrile. The solidis dissolved in isopropanol and filtered to free it of the inorganicsalt (ammonium and sodium chlorides), and then the solvent is removed toisolate the hydrochloride salt of 1-[(2 mercaptoethyl) amino]-butanol asa waxy white solid, m. 8391 C.

Calculated for C H C1NOS: C, 38.80; H, 8.69; Cl, 19.09; N, 7.54; S,17.27. Found: C, 39.1; H, 8.6; CI, 18.8; N, 7.8; S, 17.1.

Proceeding similarly, the benzylthioalkylamines mentioned above inExamples 5 and 6 are debenzylated to provide the correspondingmercaptoalkylamines.

9 EXAMPLE 8 This example describes preparation of an ester in accordancewith the invention.

Addition of 24 parts of acetyl chloride to 6 parts of providing a :1molar ratio produces spontaneous reflux of the mixture accompanied byvigorous evolution of hydrogen chloride. The resulting solution ismaintained at reflux for 2 /2 hours, after which excess acetyl chlorideis removed. Trituration of the oily residue with anhydrous etherproduces the acetate-thioacetate; of 1-[(3-mercaptopro-pyl)amino]-2-butanol hydrochloride as a white solidhaving an infrared spectrum exhibiting two strong canbonyl bands, oneattributed to the oxygen ester at 57 1. and the other to the thio esterat 5.9;.

Proceeding similarly, addition of acetyl chloride to 2 [(2methoxyethyhamino]ethanethiol produces the mono-thioacetate thereof.

To provide the mono-propionate of 2-[(2-mercaptoethyl)amino]ethanol,ethanola=mine hydrochloride is es'terified with propionic anhydride toprovide 2-arninoethanol propionate hydrochloride, this is neutralizedwith base to provide the free amine, and the resulting product is thenmercaptoethylated with ethylene sulfide in a mixed solvent systemfollowing the procedure of Example 3.

Generally similar procedures provide the mono and diesters of others ofthe presently provided amines,

EXAMPLE 9 This example illustrates use of amines provided by thisinvention.

The hydrochloride salt of l-[ (Z-mercaptoethyl) amino]- 2-propanol isdissolved in water to provide a physiologically acceptable solutionhaving a pH between 7 and 7.5, at a concentration of 3%. The solution isinjected subcutaneously into mice, at a level of 300 mg./kg. body weight(calculated on free amine), which level has previously been determinedto be well below a lethal dosage. Fifteen minutes after the injection,the injected animals are exposed to X-ray radiation, along with othermice which have received an injection of neutralized aqueous HCl, as acontrol. The test animals are then held in cages and fed and wateredwhile they are observed. At a radiation level of 600 roentgens, 55% ofthe controls are dead in from 12 to 19 days; at 825 roentgens, all thecontrols are dead in within 2 weeks. All of the animals receiving thedrug injection before exposure to the radiation, however, are alive atthe end of the full 30 day test period.

Good protective results are similarly produced using a 350-500 mg./ kg.dosage of the hydrochloride salts of 2-[ (Z-mercaptoethyl amino]ethanol,

3 (Z-mercaptoethyl) aminojl-l,2-propanediol,

l-[ (Z-mercaptoethyl) amino] -3-meth0xy-2-propanol, and 1,4-bis(Z-mercaptoethyl) amino]-2,3-butanediol.

Referring now to the scope of this invention, the monoamines providedhereby include mono-oxy and poly-oxy compounds composing the subclassesof alcohols, ethers and alkoxyalkanols.

The alcohols which are monohydric and acyclic are illustrated bymono-amines including secondary amines such as 2-[ (Z-mercaptoethyl)amino]ethanol,

2-[ (Z-mercaptopropyl) amino] ethanol,

2-[ (Z-mercaptoethyl) amino] -1-propanol,

3-[ (Z-mercaptoethyl) amino] -1-propanol,

3- (2-mercaptoethyl amino] -n-butanol,

2-[ (Z-mercaptoethyl amino1-l-butanol,

3-[ (Z-mercaptoethyl) amino] -2 -propanol,

l-[ (3-mercaptopropyl) amino] -2-propanol, l-[ (Z-mercaptodecyl) amino]-2-butanol,

l-[ (Z-rnercaptopropyl) amino] -2-butanol,

l-[ (Z-mercaptoethyl) amino] -2-octanol,

2-[ (Z-mercaptoethyl) amino] -3-ocetadecanol, 1- (Z-mercaptoet-hylamino) -2-methyl-2-propanol,

1-[ (2-mercaptoethyl)amino1-2-methyl-2-pentanol; and

tertiary amines such as 2- (Z-mercaptoethyl methyl amino ethanol,

2- (3-mercaptopropyl methylamino ethanol, 2-[nonyl Z-mercaptoethylamino] ethanol,

2- [isopropyl (Z-merc aptoethyl amino ethanol, 2- [butyl(2-mercaptoethyl amino ethanol,

and the like.

The alcohols which are monohydric and cyclic are illustrated byalicyclic mono-amines such as 2-[ (Z-mercaptoethyl) amino] cyclohexanol,2-[ (3-mercaptoethyl methylamino/cyclohexanol, and 4-ethyl-2-[(Z-mercaptoethyl) amino] cyclopentanol;

and by heterocyclic mono-amines including an exocyclic oxygen atom suchas 1-(Z-mercaptoethyl)-3-piperidinol, l-(Z-mercaptoethyl)-4-piperidinol,l-(2 mercaptoethyl)- 3-piperidinemethanol and so forth.

The class of mono-oxy mono-amines of the invention which are ethersinclude, for example 2-[ (Z-methoxyethyl) amino]ethanethiol,

2- (3-methoxypropyl) amino] ethanethiol,

2- 3 iso pro poxypropyl) amino] ethanethiol,

2-[ l-dodecoxy-Z-butyl) amino] ethanethiol,

2-[ (3-methoxy-2-butyl) amino]ethanethiol,2-[(1-methoxy-2-propylamin0]ethanethiol,

3 (Z-isopropoxypropyl) amino] prop anet-hiol,

2-[ (Z-methoxybutyl) amino] ethanethiol,

3 (2-isoamyloxybutyl amino] propanethiol,

2-[ (2-methoxyoctyl) amino]ethanethiol,

2-[ (2-isooctyloxy-3-butyl amino ethanethiol,

2- (Z-methoxy-Z-methylpropyl) amino 1 ethanethiol, 2-[(2-methoxy-2-methylpentyl) amino]ethanethiol, 2-[ (Z-methoxycyclohexylamino] ethanethiol,

2- (2-ethoxyethyl)methylamino1ethanethiol,

2-[ l-methoxy-Z-propyl)methylamino1ethanethiol, 3 (Z-met-hoxyethylmethylamino propanethiol, 2-[ (2-cyclohexyloxyethyl isopropylaminoethanethiol, 2 [butyl Z-methoxyethyl amino] hexadecanethiol, 2-(4-methoxy piperidinyl ethanethiol,

and so forth.

Still another class of mono-amines provided by this invention arepoly-oxy compounds, containing more than one connective oxygen atom.

This class is inclusive, firstly, of poly-oxy compounds comprisingpolyols. Illustrative polyols of this nature, comprisingmercaptoalkylaminoalkanepolyols, include 3 (Z-mercaptoethylamino)-1,2-propanediol,

3 (2-mercaptoethyl) amino] -1,2-butanediol,

2-[ (2-mercaptoethyl) amino] -l,3-butanediol,

3-[ (3-Inercaptopropyl amino] -1,2-propanediol,

3 (4-mercaptobutyl) amino] -l,2-propanediol,

2- [Z-mercaptoethyl) amino] 1 ,4-butanedi0l,

2-[ (3-mercaptopropyl amino] -3-methyl-1,4-butanediol,

3-[ (Z-mercaptoethyl) amino] -l,2-octadecanediol,

4- (Z-mercaptoethyl) amino] -1 ,2-cyclohexanediol,

3-[ (2mercaptoethyl methylamino] -1,2-propanediol,

2- (2-mercaptoethyl) amino] -2-(hydroxymethyl) -l ,3-

pro pancdiol,

2- (Z-mercaptoet-hyl) amino] -1 ,3-propanediol,

3 3-n1ercapto pro pyl amino] -3- (Z-hydroxyethyl 1,5 -pentanediol,

3-[ (Z-mercaptoethyl amino]- 1 ,2,4-butanetriol,

and the like.

The mono-amino poly-oxy compounds of the invention also includealkoxyalkanols such as l-[ (Z-rnercaptoethyl amino]-3-methoxy-2-propanol,

l-[ (3-mercaptopropyl) amino] -3-butoxy-2-propanol,

1-[ (Z-mercaptoethyl) amino] -3-pentoxy-2-propanol,

l- [ethyl (Z-mercaptoethyl) amino]-2-cyclohexyloxy-2- propan ol,

5-[ (2-mercaptoethy1) amino] -4-methyll-methoxy-Z- pentanol, 1-(Z-mercaptoethyl) aminornethyl] -5-hydroxypyran,

and the like; and polyethers including, for example,

2-[ (2,3-dimeth0xypropyl) amino] ethanethiol,

2- (2,3-diethoxypropyl) amino] ethanethiol,

3-[ (2,3-dimethoxypropyl) amino] propanel-thiol, 4-[(2,3-dibutoxypropyl) amino] butanel-thiol, 2-[ 1,2-dimethoxy-3 -butylamino] ethanethiol,

2- (2,3-dipentoxypr0pyl) amin0]ethanet-hiol and so forth.

The diamines of the invention include as a first classmono(mercaptoalkyl)oxyalkyl diamines which in turn includeN-mercaptoalkyl N-oxyalkyl alkylene diamines of the formulaHSR1NR3NR2(OR 2)x and N-mercaptoalkyl oxyalkylene diamines of theformula HSR -NRrNR' Ri z):

where x is 1 to 3, each R is aliphatic hydrocarbon and each R is H oraliphatic hydrocarbon as defined above.

Referring to the alkylene diamines, these include alcohols such as 3-(2- (Z-mercaptoethyl amino] ethylamino) -2- butanol,

3- (2-[ (2-mercaptoethyl) amino] l-methylpropylamino) -2-butanol,

2- 2-[ (Z-mercaptoethyl) amino] ethylamino) cyclohexanol,

and so forth; and ethers such as 2- (2- [Z-methoxyethyl) amino]-ethylamino) ethanethiol,

2- (2- (3-methoxypropyl) amino] ethylamino) ethanethiol,

2- 3 (2-propoxyethyl amino] propylamino) ethanethiol,

2- 3- (4-morpholinyl pro pyl] amino) ethanethiol,

2- 6 (methoxymethyl) aminolhexyl) amino] eth anethiol and so forth.

The oxyalkylcne diamines are illustrated by alcohols such1-dimethylamin0-3-[ (2-mercaptoethyl) amino] -2- propanol,

l-diethylamino-3-[ (Z-mercaptoethyl) amino] -2- propanol1-methylamino-3-[ (Z-mercaptoethyl) amino] -2-propanol,

and ethers such as 2- (3-dimethy1amino-Z-methoxypropyl) amino]ethanethiol,

2- Z-morpholinylmethylamino ethanethiol, 2-[(6-dimet-hylamino-3-meth0xyhexyl) amino]ethanethiol and so forth.

A further embodiment of the diamines of the invention comprisesbis(mercaptoalkyl)oxyalkylene diamines. These include alcohols which aremonohydric such as 1,3 -bis [Z-mercaptoethyl) amino] -2-propanol,1,3-bis (3-mercaptopropyl) amino] -2-methyl-2-propanol, and the like,and those which are polyhydric such as 1,4-bis[ (Z-mercaptoethyl amino]-2,3-butanediol, 1,4-bis[ (3-mercaptopropyl) amino]-2,3-butanediol,

1,5 -bis (Z-mercaptoethyl -amino] -2,4-pentanediol,

1,4-bis[ (Z-mercaptoethyl) amino] -2-methyl-2,3-

butanediol,

1,4-bis [isopropyl(Z-mercaptoethyl amino] -2, 3-

b'utanediol,

12 2,5 -'bis (3-mercaptopropy1) amino] -3,4-hexanediol, 1,4-bis(Z-mercaptoethyl) amino] -2,3-dimethyl-2,3-

butanediol, 2,5 -bis (Z-mercaptoethyl) amino] -1,3,4-hexanetrio1,1,4-bis 2-mercaptoethyl methylamino] -2,3 -butanedio1, and so forth,

The stated diamines also include, for example, alkoxyalkanols such as1,4-bis[ (Z-mercaptoethyl amino] -2-methoxy-3 -butanol, 1,4-bis[(3-mercaptopropyl) amino] -2-ethoxy-3 -butanol, 1,4-bis(Z-mercaptoethyl) amino] -3pentoxy2-butanol,

1-[ (Z-mercaptoethyl) amino] -4-[ S-mercaptopropyl) amino] -3-butoxy-2-butanol,

3,6-bis[ (Z-mercaptoethyl) amino] -5-methoxy-4-octanol,

and so forth; ethers such as N,N'-bis(Z-mercaptoethyl)-3-methoxy-1,6-

hexanediamine, and so forth.

Still another class of novel compounds provided by the invention areesters of the mercaptans of the invention, wherein a hydroxy radical, amercapto radical, or both such radicals are esterified by an acylradical of the formula RCO'-- where R is a saturated aliphatichydrocarbon radical. Thus, for example, the invention includes esterssuch as 2-[ (2-mercaptoethyl) amino] ethanol diacetate,

2-[ (B-mercaptopropyl -amino ethanol diacetate,

1-[ (Z-mercaptoethyl amino] -2-propanol diacetate,

1- (3-mercaptopropyl) amino] -2-butanol diacetate,

2-[ (Z-mercaptoethyl) amino] -4-methylcyclohexanol diacetate,

2-[is0propyl(Z-mercaptoethyl)amino]ethanol diacetate,

2-[ (2-mercaptoethyl)amino] ethanol dipropionate,

3-[ (Z-mercaptoethyl) amino] -1-propanol dibutyrate,

3- (Z-mercaptoethyl amino] -2-butanol dihexanoate,

2- (Z-mercaptoethyl) amino]ethanol dioctanoate,

2-[ (Z-acetoxyethyl) amino] ethanethiol,

2-[ (Z-acetylthioethyl amino] -ethanol,

2-[ (3-acetylthiopropyl) amino] -1-methyll-cyclohexanol,

and so forth.

Referring now to the preparation of the presently provided compounds,the useful kinds of synthetic methods for producing the aminoalkanolsand aminoalkyl ethers of the invention may be regarded as including twogeneral types. The first is a ring-opening reaction, and the second is acondensation reaction.

Ring-opening reactions are adapted to introduce mercaptoalkyl andhydroxyalkyl radicals into amines to provide the compounds of theinvention. Ring opening of ethylene sulfide may be used to supply themercaptoethyl radical, and ring opening of ethylene oxide or a likealkylene oxide, to introduce a hydroxyalkyl radical.

Thus, a convenient method for the preparation of theZ-mercaptoethylamino compounds of the invention is the reaction ofethylene sulfide with an oxyalkylene-substituted amine. This is themethod identified in the table above as Method A. For example, thereaction of 2-aminoethanol with ethylene sulfide may be employed toproduce addition with ring opening, forming2-[(2-mercaptoethyl)amino]ethanol. A difiiculty with such a synthesis isthe fact that polar hydroxyalkyl-substituted amines tend to producepolymerization of ethylene sulfide with itself, and the ethylene sulfidepolymer may contaminate the product or indeed, constitute the major orsole product of contact of ethylene sulfide with the polar amine. Thisdifficulty can, however, be overcome by a method set forth in co-pendingapplication S.N. 176,408 filed by John C. James on February 28, 1962, inaccordance with which N-mercaptoalkyl derivatives of polar amines areprepared by contacting ethylene sulfide with a polar amine in a mixedsolvent system. In accordance with this method, the ethylene sulfide isintroduced gradually into a reaction mixture comprising the oxyalkylamine and a solvent mixture of a major proportion of a solvent of lowpolarity such as benzene and a minor proportion of a solvent ofrelatively high polarity such as ethanol. It is found that thisprocedure substantially obviates formation of ethylene sulfide polymerand produces satisfactory yields of the desired 2-mercaptoethyloxyalkylamines.

The amines which may advantageously be employed in the reaction withethylene sulfide, whether polar or not, are those containing the residueof the desired product, to which the mercaptoethyl radical need merelybe added as an amine nitrogen substituent to produce the compounds ofthe invention, Thus, useful oxyalkyl amines which may be employed forreaction with ethylene sulfide to produce mercaptoalkylaminoalkanols,ethers, and the like in accordance with this invention comprise, forexample, alkanols such as Z-aminoethanol, 3-amino-1-propanol, 4-amino-l-butanol, Z-amino-l-butanol, 1-amino-2-butanol,1-amino-2-octanol, amino-tert-butanol, 1-amino-2-methyl- 2-pentanol,2-aminocyclohexanol, Z-methylaminoethanol, 2-isopropylaminoethanol,Z-piperidinol, and so forth; alkoxyalkylamines such as2-methoxyethylamine, 3-methoxypropylamine, 3-isopropoxypropylamine,l-aminomethyltetrahydropyran, and so forth; polyoxyamines such as 3-arnino-1,2-propanediol, 1-amino-2,3-butanediol, l-amino-3-methoxy-2-propanol, 1-amino-3-butoxy-2-propanol, 1-amino-3-pentoxy-2-propanol, 2-(2-methoxyethyloxy)ethylamine; andoxypolyamines such as 1-amino-3-dimethylamino-Z-propanol;4-(3-aminopropyl)morpholine, N-(2- methoxyethyl)ethylenediamine, and soforth. The products of the reaction in this case will be compoundsprovided by this invention as stated above, such as2-[(2-unercaptoethyl) amino] ethanol.

Oxyalkyl amines such as those just mentioned can also be reacted withpropylene sulfide to make the mercaptopropylamino oxyalkyl compounds ofthe invention. However, this compound, unlike ethylene sulfide, mayproduce a mixture of isomers as product. Therefore, a preferred methodof making such mercaptopropylamino compounds is the condensationreaction discussed hereinafter.

Ring-opening reactions for making the compounds of this invention,besides the ethylene sulfide reaction discussed above, include ringopening of epoxyalkanes. By epoxyalkanes is meant vic-epoxy-alkanes,where the epoxy oxygen is attached to each of two adjacent carbon atoms.They may contain one or more than one such epoxy configuration.

In preparation of the compounds of this invention, such epoxides will bereacted with an alkylamine. In general, this cannot be amercaptoalkylamine, because the mercapto group is subject to attackunder the conditions employed to react the cyclic oxide with the amine.However, if the hydrogen attached to sulfur in a mercaptoalkyl amine isreplaced by an aralkyl radical like benzyl, the sulfur atom is blockedand protected. Debenzylation can be later effected, as discussedhereinafter, to produce the corresponding mercaptan. The steps ofreaction of an epoxide with a benzylthioalkylamine followed bydebenzylation comprise the method identified on the tables above asMethod B.

Some of the products of the stated first step of Method B and of MethodC as described hereinafter are new compounds. They are described andclaimed in copending applications S.N. 176,406, S.N. 176,410, and SN.176,- 411, each filed February 28, 1962 by Robert I. Wineman, Morton H.Gollis, and 'John C. James.

Thus the presently contemplated method comprises opening the ring of avic-epoxyalkane in reaction with a. benzylthioalkylamine. The method canbe illustrated, for example, by reference to the reaction of propyleneoxide with a benzylthioalkylamine, as shown in the following equation:

where R and R are as defined above and CH is the benzyl radical. It hasbeen established that the epoxy ring opens at the least substitutedcarbon atom, so that epoxides such as 1,2-epoxypropane can be employedto produce a secondary alkanol. Polyols of the present invention can beproduced, for example, by employing a diepoxyalkane such as butadienediepoxide, or an epoxyalkanol such as glycidol. Reaction of an epoxideas herein contemplated can usefully be employed to produce (by Way ofdebenzylation of the benzylthio compound) not only the hydroxy compoundsof this invention, but also the alkoxyalkanols, by employing an alkoxyepoxy alkane as the reactant.

Thus, useful epoxides comprise vic-epoxyalkanes such as ethylene oxide,propylene oxide, 1,2-butylene oxide, 2,3-butylene oxide,2-methylpr0pylene oxide, 2-methyl-l,2-pentylene oxide, cyclohexeneoxide, butadiene diepoxide,

2, 3 4,5 -diepoxyhexane,

1,2 3 ,4-diepoxy-cyclohexane, 2,3-expoxy-l-propanol,3,4-epoxy-1-butanol, 2,3-epoxypropyl n-butyl ether, 2,3-epoxypropyl2-methylbuty1 ether, 2,3-epoxyclohexyl methyl ether, and so forth.

The benzylthioalkylamines with which the epoxy compounds may be reactedin making the presently provided compounds are benzylthioalkyl amineswherein alkyl is saturated aliphatic hydrocarbon, the amine nitrogenatom carries at least one hydrogen substituent, and any N substituentother than H is saturated aliphatic hydrocarbon. Thus, useful aminesinclude, for example 2- benzylthio ethylamine,

2- (benzylthio -N-methylethylamine,

2- (benzylthio) -N-ethylethylamine,

2- benzylthio) -N-propylethylamine,

3 (b enzylthio -1-propylamine,

2- (benzylthio) -1-butylamine,

2- benzylthio -1 -propylnonylamine,3-(benzylthio)-N-cyclohexyl-l-propylamine and so forth.

Products of such reaction will comprise, for example, 1-( [2-(benzylthio ethyl] amino -2-propanol,

l-( [2- (benzylthio ethyl] amino-3-methoxy-2-propanol,

1-( [3- (benzylthio propyl] amino) -2-propanol,

1,4-bis( [Z-(benzylthio) ethyl] amino) -2,3-butanediol,

and so forth, which can be converted to corresponding mercaptans bydebenzylation as described hereinafter.

The conditions for conducting the stated ring-opening reactions mayconsist merely of contacting the cyclic compound with the otherreactant. Reaction tends to be immediate and vigorous. The temperaturemay range from above freezing to below the decomposition temperature ofthe reaction mixture components, broadly; more particularly, holding thereaction temperature at 50 C. is favorable. The reaction may beexothermic, and dropwise addition of the cyclic compound to the reactionmixture is usually preferable.

Generally, not more than about one equivalent of the cyclic compoundwill be introduced per equivalent of amine, where one equivalent is onemole divided by the number of reactive amine groups and of epoxy groups,respectively; and less may be used, where incomplete conversion isacceptable. Solvents and diluents are desirable, and useful solvents anddiluents include, for example, hydrocarbons such as benzene and hexane;ethers such as diethyl ether and dioxane; alcohols such as methanol andethanol, and so forth. The use of a mixed solvent system for reaction ofethylene sulfide with polar amines has been mentioned above. Maintainingan atmosphere of nitrogen over the reaction mixture is useful inpreventing access of air. Atmospheric pressures are suit- 15 able,though variation of pressure above and below atmospheric may be employedif desired.

Referring now to the above-mentioned condensation reaction employed toprepare the present compounds, this is a condensation of a benzylhaloalkyl sulfide with an amino-substituted oxyalkyl compound having atleast one free amine hydrogen substituent. The condensation releaseshydrogen halide to produce a benzylthioalkylamino oxyalkyl compoundwhich can be debenzylated as described hereinafter to the correspondingmercaptoalkylamino oxyalkyl compound. This is Method C referred toabove. Useful benzyl haloalkyl sulfides includes for example, bromides,chlorides and iodides such as benzyl 2-chloroethyl sulfide, benzyl3-chloropropyl sulfide, benzyl 3-bromopropyl sulfide, benzyl 3-iodobutylsulfide, benzyl 2-chlorobuty1 sulfide, benzyl 2-chloropropyl sulfide,and so forth. Useful a-mino oxylalkyl compounds include, for example,l-amino-Z-propanol, 3-amino-l-propanol, 1-amino-3-butanol,1-amino-2-methyl-2-propanol, 1-amino-3-methyl-2-butanol, 1-methylamino-3methyl-3 butanol, 2-amino-3-hexanol, 3-amin0-2-methoxy-l-propanol,3-methoxy-l-propylamine,

3- hydroxymethyl) -piperidine, 3-amino-l,2,4-butanetriol,3-amino-l,2-propanediol, 2-amino-l,3-butanediol,

2-amino-2- (hydroxymethyl) l ,3-propanediol, 2- (methylamino) ethanol,2-(ethylamino)ethanol, 2-(propylamino)-ethanol,2-(ethylamino)-l-propanol, 2-(butylamino)-l-butanol,

2-[ (2,3-dimethylbutyl) amino] ethanol,

3- (methylamino) -2,2-dimethyl-1 -propanl, 3-methoxy-1,6-hexanediamineand so forth.

Products of the condensation of the amine with the halide willcorrespond to the mercaptans of this invention, except that a benzylthiogroup will appear in place of the mercaptan group. Thus, the productswill include, for example, amines such as N- Z-benzylthioethyl-3-hydroxypiperidine, N-(Z-benzylthioethyl)-3-hydroxy-4-pipecoline,N-(Z-benzylthioethyl)-3-methoxy-1-propylamine,

2- (3-benzylthiopropyl) amino] -ethanol and the like.

Conditions for the preparation of the compounds of the present inventionby the condensation reaction may comprise merely contacting the halidewith the amine. Their ratio may be about that of a 1:1 equivalency,calculated on the number of reactive halogen atoms and amine radicalsthey respectively contain, or an excess of either may be used.

Acid is released by the condensation reaction, and desirably the halideand amine are contacted in the presence of a base. Useful bases aresalts containing oxygen in the anion including hydroxides such as KOH,oxides such as lime, carbonates such as sodium carbonate; tertiaryamines like triethylamine and pyridine; and so forth. The amount of baseused will generally be approximately the calculated quantity needed toneutralize acid released, but more, such as up to 5 times thetheoretical equivalent, may be used if desired.

As to the other conditions of reaction, the presence of solvents ordiluents is desirable. These preferably are polar solvents, able todissolve the base, such as the dimethyl ether of diethylene glycol,alcohols such as ethanol, and so forth. The temperatures may range fromabove freezing to below the decomposition temperatures of reactionmixture components; a range of -150 C.

is generally suitable. Pressure may also vary over a wide range, such asfrom sub-atmospheric pressures of down to, say 50 millimeters Hg, up tosuperatmospheric pressures of 1000 pounds per square inch or above.Generally, atmospheric pressures are suitable. It is usually desirable,however, to maintain a nitrogen atmosphere over the surface of thereaction mixtures to avoid access of air.

Referring now to the debenzylation of the benzylthioalkylamines producedin accordance with the above described procedures, this is effected byadding sodium to a stirred solution of the S-benzyl compound in liquidammonia. Alternate addition of the sodium and the S- benzyl compound maybe used to overcome the insolubility of the higher molecular weightS-benzyl mercaptoalkylamino alkanols in liquid ammonia. Sufficient totalsodium should be used to produce and maintain the characteristic darkblue color of a sodium-liquid ammonia solution for a measurable time,such as at least about /2 hour, after the addition is complete. Theammonia may then be allowed to evaporate at ambient pressure and thenfinal traces removed under reduced pressure (water pump), after whichthe reaction mixture will be acidified. The residue, to avoid oxidation,is desirably blanketed with nitrogen until acidification isaccomplished. Acidification will be desirably preceded by addng water tothe reaction mixture, to solubilize the residue, while the reactionmixture is cooled, as for example by chilling in an ice bath. The acidused to acidify the mixture may be any strong proton donor which willform an acid salt with the amine. Desirably it will be a physiologicallyacceptable acid forming a physiologically acceptable addition salt withthe amine, adapted, for example, for use in physiological applicationssuch as administration of parenteral injections to animals. Usefulacids, including physiologically acceptable acids, for forming saltswith amines known in the art. Thus for example, such useful acidsinclude inorganic acids such as hydrochloric, sulfamic, phosphoric andnitric acids, and organic acids such as maleic, fumaric, succinic,methane-sulfonic, tartaric, citric, gluconic, itaconic andp-toluenesulfonic acids. Depending on the intended use of the product,indeed a toxic acid, such as picric, picrolonic or oxalic acid, may beused if desired. To form the addition salt, sufficient acid will beadded to provide one mole for each mole of amine groups in the product,the amount necessary for this depending on whether the product is amonoamine or a polyamine. Excess acid may be used. The acidic mixturemay now be extracted with a solvent such as ether for the removal oforganic byproducts. The acidic aqueous portion is a solution of the acidsalt of the organic amine mixed with inorganic salt, such as sodiumchloride. The organic amine salt may be separated by evaporating theaqueous acid solution under reduced pressure to dryness, and thenextracting the residue with a solvent such as an alcohol for the organicamine salt. Suitable solvents include methanol, ethanol and isopropylalcohol. Concentration of the extract separates the inorganic salts as aprecipitate which can be removed by filtration, whereupon the solventcan be removed from the filtrate to yield the amine hydrochloride.

Generally, isolation of the amine as a salt such as the hydrochloridesalt is desirable. However, if desired, the amine itself may berecovered from the debenzylation reaction mixture or may be produced bytreatment of the hydrochloride salt, made as described above, withalkali, such as NaQH, thus freeing the amine. In general, though, theacid addition salts of these amines are the desirable form thereof;because of their water solubility, they are better adapted than the freeamine for use in physiological applications such as administration ofparenteral injections to animals. For such use, the addition saltsselected will be non-toxic salts such as the hydrochloride, maleate orthe like. Practically any protonic acid can be used to form acidaddition salt, and useful acids, including physiologically acceptableacids, for forming salts with amines are known in the art.

Referring now to the further embodiment of this invention comprisingesters of the above-discussed mercaptoalkylamines, the amines aredesirably employed to make the esters in the form of the stated salts.Usual means of esterification will be employed, such as reaction of theanhydride or acid halide of the selected acid with the amine. Thus forexample, useful acyl halides include acetyl chloride, propionylchloride, butyryl chloride, caproyl chloride, capryl chloride, and soforth. Useful anhydrides include for example acetic anhydride, propionicanhydride, butyric anhydride, valeric anhydride, enanthic anhydride,caprylic anhydride and so forth. In general, the acid derivative and theamine will be contacted in the calculated theoretical amounts,approximately. The formation of the ester by reaction of the acid halideor anhydride with the amine may or may not require heating, butgenerally proceeds rapidly at temperatures below about 100 C.

The various mercaptoalkylamines, esters and their addition saltsprovided by this invention range from mobile liquids to crystallinesolids. The acid addition salts range from moderately to very soluble inlower alkanols such as methyl, ethyl and isopropyl alcohol; they arevery soluble in water, and many of them are quite hygroscopic. They areuseful for a wide variety of industrial, pharmaceutical and agriculturalapplications. They have demonstrated activity in protectingmicroorganisms and mammals against the harmful effects of ionizingradiation. The oxyalkyl portion of the molecules of these compoundsfavorably changes their solubility and biological transmission ascompared to non-oxygenated mercaptoalkylamines such as cysteamine.Administration of the present compounds may be effected by usualpharmaceutical methods. For example, simply dissolving the amine saltsin water gives a pharmaceutically acceptable solution adapted forparenteral administration by injection. Effective dosage levelsgenerally range from 350 to 500 mg. per kg. body weight, calculated inweight of free amine. The amines may if desired be combined with othermaterials such as copper compounds to achieve additional pharmaceuticaland medicinal effects; they may be administered orally, as for examplein the form of gelatin capsules and other variations within the usualskill of the pharmaceutical art may be made.

Additional uses for these compounds include application as chelatingagents, as for example to prevent metal ions from precipitating fromsolution; the compounds containing each of the AH, -OH and -NHconfigurations are especially valuable in this connection. Further, theymay be used as chemical intermediates, for example by ring closureproduced upon treatment with condensing agents such as phosphoruspentoxide, potassium bisulfate, sulfuric acid, aluminum oxide, and thelike, to prepare morpholines and thiamorpholines useful, for example, inthe preparation of dyes and of pharmaceuticals. The ethers are useful inthis connection in providing a nonreactive oxyalkyl group favoringreaction of the mercaptan radical. The tertiary amines are adapted forquaternization to provide bactericidal and detergent products. Oxyalkylcompounds of the invention including higher alkyl radicals, such as thehydrochloride salt of 2-( [3-(1-n-butylheptyloxy)propy1]amino)-ethanethiol, can be used as such assurface active agents; the stated compound, which has anomalously lowwater and high organic solvent solubility, is an unusually effectiveemulsifying agent. The mercapto and acylthiol functions of thesecompounds adapt them for use in rubber chemicals, as for example asvulcanizing and curing agents. The various products of the invention canalso be employed as agricultural toxicants, to rid soil and plant standsof undesirable vegetation, nematodes, insects and the like.

While the invention has been described with particular reference tovarious specific embodiments thereof, it is to be appreciated thatmodifications and variations can be made without departing from thescope of the invention,

18 which is limited only as defined in the appended claims.

What is claimed is:

1. The alkanoate esters of compounds selected from class consisting ofN-mercaptoalkyl oxyalkyl amines in which at least one of the oxy O andamino N atoms is exocyclic, containing from 1 to 2 amino N atoms,separated from other hetero atoms by at least two carbon atoms, in whichthe amino nitrogen substituents are selected from the class consistingof hydrogen, saturated aliphatic hydrocarbon radicals, oxyalkylradicals, and mercaptoalkyl radicals, where alkyl is saturated aliphatichydrocarbon, wherein said alkanoate esters of said mercaptoalkyloxyalkyl amines are esters with acids consisting of a saturatedaliphatic hydrocarbon radical attached to the carboxylic function ofsaid acids; and the acid addition salts of said alkanoate esters of saidamines with protonic acids; wherein each of the said saturated aliphatichydrocarbon radicals of said compounds is hydrocarbon of up to 18 carbonatoms.

2. Compounds selected from the class consisting of the alkanoate estersof mercaptoalkyl oxyalkyl amines of the formula where each R issaturated aliphatic hydrocarbon,

each R is selected from the class consisting of hydrogen and saturatedaliphatic hydrocarbon, and x is an integer of from 1 to 3 and N isseparated from other hetero atoms by at least two carbon atoms; whereineach of said saturated aliphatic hydrocarbon radicals contains up to 18carbon atoms, and the said alkanoate esters are esters with acidsconsisting of a saturated aliphatic hydrocarbon radical of up to 18carbon atoms attached to the carboxylic function of said acids; and theacid addition salts of said alkanoate esters with protonic acids.

3. Compounds selected from the class consisting of the alkanoate estersof mercaptoalkyl oxyalkyl diamincs of the formula where each R issaturated aliphatic hydrocarbon,

each R is selected from the class consisting of hydrogen and saturatedaliphatic hydrocarbon, and x is an integer of from 1 to 3, at least oneof the oxy O and amino N atoms is exocyclic, and N is separated fromother hetero atoms by at least two carbon atoms; wherein each of saidsaturated aliphatic hydrocarbon radicals contains up to 18 carbon atoms,and said alkanoate esters are esters with acids consisting of asaturated aliphatic hydrocarbon radical of up to 18 carbon atomsattached to the carboxylic function of said acids; and the acid additionsalts of said alkanoate esters with protonic acids. 4. Compoundsselected from the class consisting of the alkanoate esters ofmercaptoalkyl oxyalkyl amines of the formula at least one of the oxy Oand amino N atoms is exocyclic,

19 20 and N is separated from other hetero atoms by at least at leastone of the oxy O and amino N atoms is exotwo carbon atoms; cyclic,wherein each of said saturated aliphatic hydrocarbon radiand N isseparated from other hetero atoms by at least cals contains up to 18carbon atoms, and the said altwo carbon atoms; kanoate esters are esterswith acids consisting of a sat- 5 wherein each of said saturatedaliphatic hydrocarbon radiurated aliphatic hydrocarbon radical of up to18 carbon cals contains up to 18 carbon atoms, and the said esters atomsattached to the carboxylic function of said acids; are esters with acidsconsisting of a saturated aliphatic and hydrocarbon radical of up to 18carbon atoms attached the acid addition salts of said alkanoate esterswith proto the carboxylic function of said acids; and the acid adtonicacids. 10 dition salts of said alkanoate esters with protonic acids. 5.Compounds selected from the class consisting of the 6.1-[(3-mercaptopropyl)amino] 2 butanol acetatealkanoate esters ofmercaptoalkyl oxyalkyl diamines of thioacetate hydrochloride.

the formula (H s R1 N a R2(O R12) x References Clted 15 UNITED STATESPATENTS 2,976,215 3/61 Kalopissi et. a1 260-455 XR where each R issaturated aliphatic hydrocarbon,

each R' is selected from the class consisting of hydro- CHARLES PARKERPnmary Exammer' gen and saturated aliphatic hydrocarbon, 20 D, R,PHILLIPS, Assistant Examiner. and x is an integer of from 1 to 3,

1. THE ALKANOATE ESTERS OF COMPOUNDS SELECTED FROM CLASS CONSISTING OFN-MERCAPTOALKYL OXYALKYL AMINES IN WHICH AT LEAST ONE OF THE OXY O ANDAMINO N ATOMS IS EXOCYCLIC, CONTAINING FROM 1 TO 2 AMINO N ATOMS,SEPARATED FROM OTHER HETERO ATOMS BY AT LEAST TWO CARBON ATOMS, IN WHICHTHE AMINO NITROGEN SUBSTITUENTS ARE SELECTED FROM THE CLASS CONSISTINGOF HYDROGEN, SATURATED ALIPHATIC HYDROCARBON RADICALS, OXYALKYLRADICALS, AND MERCAPTOALKYL RADICALS, WHERE ALKYL IS SATURATED ALIPHATICHYDROCARBON, WHEREIN SAID ALKANOATE ESTERS OF SAID MERCAPTOALKYLOXYALKYL AMINES ARE ESTERS WITH ACIDS CONSISTING OF A SATURATEDALIPHATIC HYDROCARBON RADICAL ATTACHED TO THE CARBOXYLIC FUNCTION OFSAID ACIDS; AND THE ACID ADDITION SALTS OF SAID ALKANOATE ESTERS OF SAIDAMINES WITH PORTONIC ACIDS; WHEREIN EACH OF THE SAID SATURATED ALIPHATICHYDROCARBON RADICALS OF SAID COMPOUNDS IS HYDROCARBON OF UP TO 18 CARBONATOMS.